Field of the Invention
The present invention relates to a process for a preparation of N-substituted-hydroxycycloalkylamine derivatives and more particularly, to the process for the preparation of N-substituted-hydroxycycloalkylamine derivatives represented in the following formula (1), regioselectively in high yield via 1,2-cyclosulfinylalkyl halide as an intermediate from the 1,2-dihydroxyalkyl alcohol as a starting material. Moreover, the synthetic method in this invention effectively provides optically active N-substituted-hydroxycycloalkylamine derivatives in high purity with regioselectivity and stereoselectivity, as well as racemic compounds, when optically active 1,2-dihydroxyalkyl alcohol is used as a starting material. 
wherein,
* represents an asymmetric carbon;
R1 is hydrogen or typical amino-protecting groups such as linear alkyl, branched alkyl, or cycloalkyl containing 1xcx9c10 carbon atoms or aromatic hydrocarbons;
R2 is hydrogen or hydroxyl group;
R3 is hydrogen or hydroxymethyl group; and
n is 1 or 2.
N-substituted-hydroxycycloalkylamine derivatives are widely used as the intermediates for the synthesis of various organic compounds as well as pharmaceutical and agrochemical compounds. Especially, the optically active (R)- or (S)-N-substituted-3-hydroxypyrrolidine is generally known as the key intermediate in the preparation of pharmaceutical and agrochemical compounds. For example, the optically active N-substituted-3-hydroxypyrrolidine is used as the essential intermediate for the preparation of various pharmaceuticals such as carbapenem antibiotic (Panipenem), vasodilatin (Barnidipine), or antihypertensive in developing (Darifenacine, Lirequilli Clinafloxacine) [EP No. 483,580, No. 330,469, No. 304,087; U.S. Pat. Nos. 5,463,064, 5,364,872, 5,281,711, 5,109,008, 4,916,141; International Patent WO 91/09013].
Several methods for the preparation of optically active 3-hydroxypyrrolidine derivatives have been reported as introduced hereinafter.
One of the most general methods for the preparation of N-substituted-3-hydroxypyrrolidine is the reduction of N-benzyl-3-hydroxysuccinimide using the reducing agent, lithium aluminum hydride (LAH), which is prepared by the reaction of d- or l-malic acid and benzyl amine [Synthetic Communications, 1983, 13(13), 1171xcx9c1123; Synthetic Communications, 1985, 15(7), 587xcx9c598; U.S. Pat. Nos. 5,109,008, 4,705,853].
Another method for the synthesis of N-substituted-3-hydroxypyrrolidine is the decarboxylation of (2S, 4R)-(xe2x88x92)-4-hydroxy-2-pyrrolidine carboxylic acid [International Patent WO 91/09013, U.S. Pat. No. 5,233,053].
Another method is the preparation of (S)-3-hydroxypyrrolidine by reduction of (S)-3-hydroxypyrrolidine derivatives developed by Eugene J. Trybulsky [U.S. Pat. No. 4,937,235].
However, the above conventional methods are not adequate to be introduced to industrial process, because of the delicate synthetic process, low yield, and expensive raw materials and reagents.
The preparation of (S)-3-hydroxypyrrolidine with hydroxybutyronitrile compounds has been reported [EP No. 269,258]. This method is effective on the preparation of 3-hydroxypyrrolidine as a racemic mixture. However, it can be hardly applied to industrial process, because the optically active 3-hydroxybutyro-4-nitrile, a key intermediate in the synthetic process of optically pure 3-hydroxypyrrolidine, is not easily prepared.
Inou and coworkers reported the preparation of 3-hydroxypyrolidine from 4-chloro-3-hydroxybutyronitrile [EP No. 347,818]. According to this method, 3-hydroxypyrrolidine is prepared from (R)-2-acetoxy-3-chloropropyltosylate which is obtained by enzyme-mediated stereoselective hydrolysis of racemic epichlorohydrine. But, it has many problems to be utilized in industry because of the multi-step procedures and low yield.
Besides, several biochemical methods have been reported [JP Pyung 5-227991, Pyung 6-141876]: For example, the preparation of optically active N-substituted-3-hydroxypyrrolidine by selective deacetylation of racemic 3-acetoxy-N-benzylpyrrolidine using Lipase PS [Bull. Chem. Soc. Jpn., 1996, 69, 207xcx9c215], and the preparation of optically active N-substituted-3-hydroxypyrrolidine by enzyme-mediated stereoselective hydrolysis of N-substituted-3-acyloxypyrrolidine [International Patent WO 95/03421]. However, the application of the aforesaid biochemical synthetic process to industry needs to improve the process for the recovery of enzyme and separation/purification of reaction mixtures.
Also, the preparation of N-substituted-3-hydroxypyrrolidine from 1,2,4-butanetriol or its derivatives is reported, as described hereinafter [Heterocycles, 1987, 26 (8), 2247xcx9c2265].
Initially, 1,4-dibromo-2-butanol is prepared by the reaction of 1,2,4-butanetriol with hydrogen bromide via selective bromination of only primary alcohol at the position of C1 and C4, then reacted with benzyl amine and cyclized to yield N-benzyl-3-hydroxypyrrolidine [J. Med. Pharm. Chem., 1959, 1, 76]. But, the aforesaid bromination is not controlled easily, with very low yield of 31% and use of expensive bromination reagents.
The optically active 3-hydroxypyrrolidine is prepared from the optically active 4-halo-3-hydroxybutanol [EP No. 452,143, U.S. Pat. No. 5,144,042]. According to this method, the reduction of the ester of (S)-4-chloro-3-hydroxybutylic acid with calcium borohydride provides (S)-4-chloro-1,3-butanediol, and the subsequent selective sulfonylation of the only primary alcohol using methanesulfonyl chloride followed by the reaction with benzyl amine gives (S)-N-benzyl-3-hydroxypyrrolidine. In this process, it can""t be considered as an economical method because the selective sulfonylation of only primary alcohol is difficult to result in good yield.
Moreover, the method for the preparation of the optically active N-benzyl-3-hydroxypyrolidine by optical resolution is reported [JP Pyung 9-263578, Pyung 5-336992]. But, this process may not be recommended to prepare optically active compounds in high purity at the viewpoint of economics and efficiency.
Besides, other methods have been reported [EP No. 431,521].
Even though there are various methods for the preparation of optically active N-substituted-3-hydroxypyrrolidine derivatives as described above, it has been urgent to develop the method for the efficient preparation of cycloamine derivatives via cyclization of alkyltriol with higher yield and purity than those in the conventional methods.
The inventors in this invention have investigated for a long time that an efficient synthetic method for N-substituted-hydroxycycloalkylamine derivatives from 1,2-dihydroxyalkyl alcohol and eventually realized that the three hydroxyl groups, of the starting material, 1,2-dihydroxyalkyl alcohol, should be distinguished each other from the reactivity in the nucleophilic substitution.
To fit this requirement, both of the hydroxyl groups at C1, C2 positions of 1,2-dihydroxyalkyl alcohol were converted to a cyclic sulfite group by the reaction of 1,2-dihydroxyalkyl alcohol with thionyl chloride. The subsequent conversion of terminal hydroxyl group to halide provided 1,2-cyclosulfinylalkyl halide of which the functional groups showed different reactivities. Eventually, N-substituted-hydroxycycloalkylamine derivatives were prepared by the cyclosubstitution of the aforesaid alkyl halide with nucleophile such as amine compounds. Especially, optically active N-substituted-hydroxycycloalkylamine could be prepared in high purity with regioselectivity and stereoselectivity, if the optically pure 1,2-dihydroxyalkyl alcohol was used as a starting material.
Therefore, the purpose of this invention is to provide the synthetic method of racemic or optically active N-substituted-hydroxycycloalkylamine, as the target product, in maximum yield as well as high purity simultaneously inhibiting the side-reaction, racemization or formation of isomers which are usual problems in the conventional methods.
This invention relates to the method for the preparation of racemic or optically active N-substituted-hydroxycycloalkylamine derivatives and the salts thereof represented in the following formula (1), which is characterized by the cyclosubstitution of nucleophile selected from the amine compounds represented in the following formula 4 to the racemic or optically active intermediate, 1,2-cyclosulfinylalkyl halide, represented in the following formula 3, which is prepared by the reaction of thionyl halide and 1,2-dihydroxyalkyl alcohol represented in the following formula (2) as a starting material. 
wherein, * represents an asymmetric carbon; X is halogen; R1 is hydrogen, linear alkyl, branched alkyl, or cycloalkyl containing 1xcx9c10 carbon atoms or typical amino-protecting groups such as aromatic hydrocarbons; R2 is hydrogen or hydroxyl group; R3 is hydrogen, hydroxymethyl group; n is 1 or 2; m is an integer of 1xcx9c3.
The present invention is explained in more detail as set forth hereunder.
The present invention is composed of the following mechanisms: Among three hydroxyl groups of 1,2-dihydroxyalkyl alcohol, adjacent hydroxyl groups at 1- and 2-positions are activated by the conversion to cyclosulfinyl group which is a electrophilic protecting group. The terminal hydroxyl group is substituted with a halide providing more susceptible electrophilic site than the above cyclosulfinyl group, thus this halide is preferentially reacted with the nucleophilic amine to provide secondary amine, and then intramolecular cyclization occurs via the reaction of the amine with the electrophilic sulfinyl protecting group. The basic technique consisting of this invention is the intramolecular cyclization via nucleophilic substitution at the C1 or C2 position of the cyclic sulfinyl group with regioselectivity and stereoselectivity depending on the number of carbon in the secondary amine.
In the present invention, the intermediate represented in the aforesaid formula 3 is characteristically prepared by the sulfinylhalogenation in a specific condition using the thionyl halide, as a sulfinylhalogenation agent, which is relatively cheap and allows easy control of the reaction. Thus, the subsequent cyclization proceeds in high regioselectivity and stereselectivity.
The synthetic method in this invention is applied to the preparation of racemic N-substituted-hydroxycycloalkylamine derivatives and salts thereof. Also, it can produce optically pure N-substituted-hydroxycycloalkylamine derivatives and salts thereof in high yield without racemization if optically active 1,2-dihydroxyalkyl alcohol shown in the aforesaid formula (2) is used as a starting material.
The procedure described in this invention for the preparation of racemic or optically active N-substituted-hydroxycycloalkylamine is briefly shown in the following reaction scheme 1. 
wherein, *, X, R1, R2, R3, m, and n are respectively defined as the above-mentioned.
According to the above reaction scheme 1, the reaction of 1,2-dihydroxyalkyl alcohol represented in the above formula (2) with thionyl halide in the presence of base catalyst generates 1,2-cyclosulfinylalkyl halide represented in the above formula (3). To prepare the intermediate represented in the above formula (3) in higher yield and purity, the starting material represented in the above formula (2) is dissolved in aprotic polar solvent in the presence of base catalyst, then is slowly added thionyl halide at low temperature, desirable at xe2x88x9220xc2x0 C.xcx9c10xc2x0 C.
The halide is selected from F, Cl, Br, or I, more specifically Cl or Br is recommendable. Among the thionyl halide, thionyl chloride and thionyl bromide are commercially available. Thionyl chloride is recommended due to easy purchase in large scale and less heat generation during the reaction.
The amount of thionyl halide and base catalyst and the reaction temperature should be controlled to give high yield in the synthesis of the above intermediate. Of the excess amount of thionyl halide is used, then the large amount of by-products is formed, such as trihaloalkane due to the halogenation of all 1-, 2- and terminal hydroxyl groups. Thus, 2xcx9c4 (specifically 2xcx9c2.5) equivalents of thionyl halide is recommended to be used.
The solvent used in the present invention for the synthesis of intermediate includes aprotic organic solvents such as acetonitrile, methylene chloride, chloroform, carbon tetrachloride, and diethyl ether. Among them, acetonitrile, methylene chloride or chloroform is more desirable.
Either organic or inorganic salts can be used as a base catalyst even in excess amount. Both organic base such as triethylamine, tripropylamine, N,N-diisopropylamine, pyridine and the inorganic base such as potassium hydroxide, sodium carbonate, and potassium carbonate are desirable as base catalysts. Especially, it is recommended to use 2xcx9c3 equivalents of pyridine.
After the completion of the aforesaid reaction, the reaction mixture is filtrated to remove solids and added non-hydrophilic organic solvent, recommended methylene chloride or chloroform, then washed, in succession, with water and aqueous sodium hydrogen carbonate (a weak base) to remove remained acids. The evaporation of the solvent under reduced pressure provides pale yellowish liquid, which is then subjected to simple vacuum distillation to give racemic or optically active 1,2-cyclosulfinylalkyl halide as colorless liquid in high yield as well as purity, represented in the aforesaid formula (3).
The intermediate, 1,2-cyclosulfinylalkyl halide as shown in the above formula (3), is stable for a few months at the room temperature.
The racemic or optically active N-substituted-hydroxypyrrolidine derivatives represented in the above formula (1) is effectively prepared from the intermediate, 1,2-cyclosulfinylalkyl halide, represented in the formula (3) via the following procedures.
The racemic or optically active 1,2-cyclosulfinylalkyl halide represented in the above formula (3) is dissolved in aprotic polar solvent and cyclosubstituted by the reaction with amine in the presence of base catalyst. The cyclosubstitution is performed in the range of 0xc2x0 C.xcx9c200xc2x0 C., being recommended to reflux under the pressure ranged 1xcx9c10 atm depending on the amine. The organic solvent used in the cyclosubstitution includes a polar solvent such as acetonitrile, toluene, dimethylformamide, dimethylacetamide, dioxane, tetrahydrofuran, or pyridine. Among them, acetonitrile and dimethylacetamide are desirable. The basic catalysts include either organic base such as pyridine, triethylamine, diisopropylethylamine or the inorganic base such as sodium carbonate, potassium carbonate, calcium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium methoxide, and sodium ethoxide. Among them, sodium carbonate and potassium carbonate are recommended.
The amine compounds participated in the cyclosustitution step as a reagent, are represented in the above formula (4). The more specific amine compound represented in the above formula (4) includes the alkylamines such as ammonia, methylamine, ethylamine, n-propylamine, iso-propylamine, n-butylamine, iso-butylamine, sec-butylamine, and the cycloalkylamine such cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine, and finally the aromatic amines such as phenylamine, benzylamine, methylbenzylamine, methoxybenzylamine, nitorbenzylamine, and optically active (S)- or (R)-methylbenzylamine. Besides, the typical amino protecting groups are included.
The desirable amount of the amine shown in the above formula (4) is in the range 1xcx9c10 equivalents for the efficient process.
For the efficient cyclosubstitution in this invention, a proper pressure and temperature were required. Consequently, the reaction was run for 2xcx9c48 hrs. The scheme 2 represents an example of the cyclosubstitution in this invention. The reaction of cyclosulfinylbutyl halide as represented in the above formula (3) with the benzylamine as represented in the above formula (4) for the cyclosubstitution gives N-benzyl-3-hydroxypyrrolidine as a main product without by-products such as an azidridine or azetidine compound. 
wherein, * represents an unsymmetrical carbon: X is halogen: Bz is benzyl group.
The following scheme 3 represents another example of the cyclosubstitution in this invention. The reaction of the cyclosulfinylpentyl halide as shown in the aforesaid formula (3) with the benzylamine for the cyclosubstitution provides N-benzyl-3-hydroxypiperidine as the major product and the N-benzyl-2-hydroxymethylpyrrolidine as minor product. 
wherein, * represents an unsymmetrical carbon: X is halogen: Bz is benzyl group.
The following scheme 4 represents another example of the cyclosubstitution in this invention. The reaction of the cyclosulfinylhexyl halide as shown in the aforesaid formula (3) with the benzylamine for the cyclosubstitution provides N-benzyl-2-hydroxymethyl-piperidine as the major product. 
wherein, * represents an unsymmetrical carbon: X is halogen: Bz is benzyl group.
The optically active N-substituted-hydroxycycloalkylamine derivatives are obtained from the cyclosubstitution using optically active cyclosulfinylalkyl halides as shown the above examples. The reaction of (S)-1,2-cyclosulfinyl-4-butylchloride or bromide with ammonia in high-pressure reactor for the cyclosubstitution also generated (S)-3-hydroxypyrrolidine in high yield.
Based on the aforesaid results, it is believed that the cycloalkylamine is formed by the nucleophilic substitution of amine (benzylamine) with the halide group in 1,2-cyclosulfinylalkyl halide followed by the intramolecular nucleophilic cyclization. Thermodynamically more stable cycloalkylamine is formed preferentially.
As described in this invention, the preparation of the cyclosulfinylalkyl halide, the intermediate for the cyclosubstitution as represented in the aforesaid formula (3), is advantageous over the conventional methods due to the short steps to run. With cyclosulfinylbutyl and cyclosulfinylhexyl halide, the optically pure and expensive (S)- or (R)-N-substituted-hydroxypyrrolidine and (S)- or (R)-N-substituted-hydroxymethylpiperidine derivatives, respectively, can be prepared in high yield and purity.
The synthetic methods described in this invention can provide the optically active (S)- or (R)-N-substituted-cycloalkylamine derivatives, without mentioning the racemate thereof, by using an optically active (S)- or (R)-1,2-hydroxyalkyl alcohol as a starting material. Besides, thionyl chloride used as a halogenating agent is economically advantage over the hydrogen bromide, since the thionyl chloride has the relatively low molecular weight compared to other protecting groups. Also, cyclosulfinyl group reacts and releases as sulfur dioxide upon the reaction progress, thereby enable the easy handling and separation of the gas by simple trapping resulting in small amount of waste.
Some of optically active 1,2-cyclosulfinylalkyl halides are reported in recent literatures as following.
Hercouet and coworkers used (S)-1,2-cyclosulfinyl-4-butyl chloride and 1,2-cyclosulfinyl-5-pentyl chloride as only an intermediate to prepare the cyclosulfate derivatives by simple oxidation in the synthesis of (xe2x88x92)-(2S, 3R)-methanepyrroline or (xe2x88x92)-(2S, 3R)-methanopipecolic acid [Tetrahedron: Asymmetry, 1996, 7(5), 1267xcx9c1268: Tetrahedron Letters, 1996, 37(26), 4529xcx9c4532]. Besides, the cyclosulfinyl groups are used as the simple protection group or the starting material for the preparation of the cyclic sulfate. But, it is not many cases for the purpose of nucleophilic substitution [J. Am. Chem. Soc., 1998, 110, 7538xcx9c7539; Tetrahedron: Asymmnetry, 1996, 7(8), 2411xcx9c2416: Synthesis, 1992, 1035xcx9c1052; Nucleic Acid Res., 1978, 5(3), 1029xcx9c1033: Chem. Pharm. Bull., 1977, 2181; Bull. Chem. Soc. Japan, 1975, 48(11), 3243; Chem. Rev., 1963, 63, 557xcx9c571].
The following specific examples are intended to be illustrative to the invention and should be construed as limiting the scope of the invention as defined by appended claims.